1. Field of the Invention
The present invention relates to novel anti-inflammatory and anti-allergic compounds of the glucocorticosteroid series, methods of preparing such a compound, and pharmaceutical compositions which contain such a compound. The present invention also relates to combinations of such a compound and another active agent and to therapeutic uses of such a compound. More particularly, the present invention relates to glucocorticosteroids that are derivatives of pyrrolidine.
2. Discussion of the Background
Corticosteroids are potent anti-inflammatory agents, able to decrease the number, activity, and movement of inflammatory cells. Corticosteroids are commonly used to treat a wide range of chronic and acute inflammatory conditions including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases.
Corticosteroids mediate their effects through the glucocorticoid receptor (GR). The binding of corticosteroids to GR induces its nuclear translocation which, in turn, affects a number of downstream pathways via DNA-binding-dependent (e.g. transactivation) and DNA-binding-independent (e.g. transrepression) mechanisms.
Corticosteroids for treating chronic inflammatory conditions in the lung such as asthma and COPD are currently administered through inhalation. One of the advantages of employing inhaled corticosteroids (ICS) is the possibility of delivering the drug directly at the site of action, limiting systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
Although ICS treatment can yield important benefits, especially in asthma, it is important to minimize ICS systemic exposure which leads to the occurrence and severity of unwanted side effects that may be associated with chronic administration. Moreover, the limited duration of action of ICS currently available in the clinical practice contributes to suboptimal management of the disease. While the inhaler technology is the key point to target the lung, the modulation of the substituents on the corticosteroids molecular scaffold is important for the optimization of pharmacokinetic and pharmacodynamic properties in order to decrease oral bioavailability, confine pharmacological activity only in the lung (prodrugs and soft drugs) and increase systemic clearance. Moreover, long lasting ICS activity in the lung is highly desirable as once daily administration of ICS would allow the reduction of the frequency of administration and, thus, substantially improve patient compliance and, as a result, disease management and control. In sum, there is a pressing medical need for developing ICS with improved pharmacokinetic and pharmacodynamic characteristics.
Fluticasone furoate is an example of an enhanced affinity glucocorticoid that has been developed as topical therapy for allergic rhinitis with a unique combination of pharmacodynamic and physicochemical properties which render this compound long acting in the lung and rapidly inactivated by hepatic metabolism to reduce systemic side effects (Salter M, Biggadike K, Clackers M, et al. Fluticasone furoate (FF): enhanced cellular and tissue protection with a new selective glucocorticoid agonist [abstract no P212] Ann Allergy Asthma Immunol. 2007; 98:A89, which is incorporated herein by reference in its entirety).
Glucocorticoid pyrrolidine derivatives have not been described, except for the co-pending patent application PCT/EP2011/051537, which is incorporated herein by reference in its entirety, in which some pyrrolidine derivatives were described.
Thus, there remains a need for glucocorticoids with improved properties.